Omlonti
omidenepag isopropyl
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“The general toxicology study package spans two species: two topical ocular monkey studies, and a series of subcutaneous-route studies in the Sprague Dawley rat.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“The GLP rat 26-week subcutaneous toxicity study with omidenepag isopropyl did not identify a NOAEL, because rare tumors were observed with treatment.”
Species: general tox
Cynomolgus monkey (topical ocular) and Sprague Dawley rat (subcutaneous)
“The general toxicology study package spans two species: two topical ocular monkey studies, and a series of subcutaneous-route studies in the Sprague Dawley rat.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“The Applicant submitted one fertility and early embryonic development (FEED) study (rat), two embryofetal development (EFD) studies (rat and rabbit), and one pre-/post-natal development (PPND) study (rat).”
Species: carcinogenicity
Not conducted (no lifetime rodent studies); tumors seen in 26-week subcutaneous rat study
“Lifetime rodent studies have not been performed to evaluate the carcinogenic potential of omidenepag isopropyl or omidenepag. In rats dosed by subcutaneous injection daily for 26 weeks, nephroblastoma and a spermatic cord tumor were found at 0.003 mg/kg/day”
Surrogate used in
No surrogate used
“The GLP rat 26-week subcutaneous toxicity study with omidenepag isopropyl did not identify a NOAEL, because rare tumors were observed with treatment.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey topical ocular)
“The GLP monkey 39-week topical ocular toxicity study with omidenepag isopropyl did not identify a NOAEL.”
Pivotal GLP studies
Two topical ocular monkey studies and a series of subcutaneous rat studies
“The general toxicology study package spans two species: two topical ocular monkey studies, and a series of subcutaneous-route studies in the Sprague Dawley rat.”
Route in tox
Topical ocular (monkey); subcutaneous (rat)
“The general toxicology study package spans two species: two topical ocular monkey studies, and a series of subcutaneous-route studies in the Sprague Dawley rat.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and in vivo micronucleus; positive (mutagenic and clastogenic) in in vitro mouse lymphoma assay
“Omidenepag was not mutagenic in the bacterial reverse mutation (Ames) test and the in vivo mouse micronucleus test. Omidenepag isopropyl was positive (mutagenic and clastogenic) without metabolic activation in the in vitro mouse lymphoma forward mutation assay.”
Carcinogenicity
Lifetime rodent studies not conducted; nephroblastoma and spermatic cord tumor in 26-week rat subcutaneous study
“Lifetime rodent studies have not been performed to evaluate the carcinogenic potential of omidenepag isopropyl or omidenepag. In rats dosed by subcutaneous injection daily for 26 weeks, nephroblastoma and a spermatic cord tumor were found at 0.003 mg/kg/day (33 times the RHOD based on the estimated area under the curve [AUC]).”
Reproductive & developmental
Rabbit EFD: fetal skeletal anomalies at 24x clinical exposure; not teratogenic in rats
“In animal reproduction studies, subcutaneous administration of omidenepag isopropyl to pregnant rabbits throughout the period of organogenesis produced fetal skeletal anomalies at a dose of 24 times the clinical dose, based on estimated plasma C max .”
Safety pharmacology
Dog inhalation study: no CV effect at 0.268 mg/kg/day; at ≥1.02 mg/kg raised heart rate, shortened PR, lowered blood pressure, prolonged QTc
“For in-life cardiovascular safety pharmacology endpoints, 0.268 mg/kg/day did not have an apparent effect. Doses ≥ 1.02 mg/kg of omidenepag caused increased heart rate, shortened PR interval, decreased blood pressure, and prolonged QTc.”
Genotox: Ames
Bacterial reverse mutation test judged inadequate by FDA reviewer
“Inadequate bacterial reverse mutation test”
Genotox: in vitro mammalian
Mouse lymphoma assay: positive (mutagenic and clastogenic) without metabolic activation
“Omidenepag isopropyl was positive (mutagenic and clastogenic) without metabolic activation in the in vitro mouse lymphoma forward mutation assay.”
Genotox: in vivo
Rat micronucleus: wholly inadequate per FDA (dose selection too low)
“The study is wholly inadequate to evaluate potential clastogenicity, because dose selection was too low to adequately characterize potential activity.”
Carcinogenicity model
Not conducted; 26-week sc rat study: nephroblastoma and spermatic cord tumor at 0.003 mg/kg/day (33x RHOD AUC)
“Lifetime rodent studies have not been performed to evaluate the carcinogenic potential of omidenepag isopropyl or omidenepag. In rats dosed by subcutaneous injection daily for 26 weeks, nephroblastoma and a spermatic cord tumor were found at 0.003 mg/kg/day (33 times the RHOD based on the estimated area under the curve [AUC]).”
Carcinogenicity timing
Carcinogenicity studies not conducted with omidenepag isopropyl or omidenepag
“Carcinogenicity testing has not been performed with omidenepag isopropyl or omidenepag.”
hERG / QT
Dog inhalation CV study not concerning for ocular dosing: ~150x systemic exposure margin (Cmax and AUC)
“These results are not concerning for topical ocular dosing, based on the systemic exposure margin (approximately 150 x from the low-dose TK means to the clinical PK means for both Cmax and AUC).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Omlonti don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey 13-week: no NOAEL; LOAEL 0.9 µg/eye/day based on nasal cavity findings (FDA pharmacology/toxicology review, p. 190)
NOAEL / key findings
Monkey 13-week: no NOAEL; LOAEL 0.9 µg/eye/day based on nasal cavity findings
“No NOAEL. The low dose, 0.9 µg/eye/day is the LOAEL, based on two findings in the nasal cavity:”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Monkey eye: highest in cornea and conjunctiva, lower in iris, ciliary body and choroid-RPE; plasma and blood lowest
“Distribution was: cornea > bulbar conjunctiva > trabecular meshwork > palpebral conjunctiva > sclera > aqueous humor > iris > ciliary body > choroid-retinal pigmented epithelium (RPE) > plasma > blood.”
Modality-specific risk
Rare tumors in 26-week rat study and nasal cavity metaplasia in monkeys (carcinogenic potential)
“As noted above, the 26-week sc rat study detected rare tumors after dosing with omidenepag isopropyl, and the monkey topical ocular studies detected nasal cavity metaplasia.”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
- Pigmentation
- Eyelash Changes
- Ocular Inflammation
- Macular Edema
- Risk of Contamination and Potential Injury to the Eye
Ocular toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Omlonti don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey 13-week: no NOAEL; LOAEL 0.9 µg/eye/day based on nasal cavity findings (FDA pharmacology/toxicology review, p. 190)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey topical ocular study with 4-week recovery
“A 39-week ocular toxicity study of DE-117 ophthalmic solution in cynomolgus monkeys with a recovery period of 4 weeks”
Pivotal GLP studies
Two topical ocular monkey studies and a series of subcutaneous rat studies
“The general toxicology study package spans two species: two topical ocular monkey studies, and a series of subcutaneous-route studies in the Sprague Dawley rat.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“The Applicant submitted one fertility and early embryonic development (FEED) study (rat), two embryofetal development (EFD) studies (rat and rabbit), and one pre-/post-natal development (PPND) study (rat).”
Reproductive & developmental
Rabbit EFD: fetal skeletal anomalies at 24x clinical exposure; not teratogenic in rats
“In animal reproduction studies, subcutaneous administration of omidenepag isopropyl to pregnant rabbits throughout the period of organogenesis produced fetal skeletal anomalies at a dose of 24 times the clinical dose, based on estimated plasma C max .”
PPND / ePPND: when
PPND in rat (subcutaneous) completed and submitted with the NDA
“The Applicant submitted one fertility and early embryonic development (FEED) study (rat), two embryofetal development (EFD) studies (rat and rabbit), and one pre-/post-natal development (PPND) study (rat).”
Carcinogenicity
Species: carcinogenicity
Not conducted (no lifetime rodent studies); tumors seen in 26-week subcutaneous rat study
“Lifetime rodent studies have not been performed to evaluate the carcinogenic potential of omidenepag isopropyl or omidenepag. In rats dosed by subcutaneous injection daily for 26 weeks, nephroblastoma and a spermatic cord tumor were found at 0.003 mg/kg/day”
Carcinogenicity model
Not conducted; 26-week sc rat study: nephroblastoma and spermatic cord tumor at 0.003 mg/kg/day (33x RHOD AUC)
“Lifetime rodent studies have not been performed to evaluate the carcinogenic potential of omidenepag isopropyl or omidenepag. In rats dosed by subcutaneous injection daily for 26 weeks, nephroblastoma and a spermatic cord tumor were found at 0.003 mg/kg/day (33 times the RHOD based on the estimated area under the curve [AUC]).”
Carcinogenicity timing
Carcinogenicity studies not conducted with omidenepag isopropyl or omidenepag
“Carcinogenicity testing has not been performed with omidenepag isopropyl or omidenepag.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL in monkey topical ocular studies; LOAEL 0.9 µg/eye/day (nasal cavity findings)
“No NOAEL. The low dose, 0.9 µg/eye/day is the LOAEL, based on two findings in the nasal cavity:”
NOAEL / key findings
Monkey 13-week: no NOAEL; LOAEL 0.9 µg/eye/day based on nasal cavity findings
“No NOAEL. The low dose, 0.9 µg/eye/day is the LOAEL, based on two findings in the nasal cavity:”
Efficacy evidenceopen answer page →
Efficacy evidence
IOP lowering in normotensive rabbits and monkeys and in a monkey model of ocular hypertension
“Topical ocular omidenepag isopropyl decreased IOP in ocular normotensive rabbits and monkeys, and in a monkey model of ocular hypertension.”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
FDA: intravitreal monkey study supports IOP-lowering proof of concept
“The study provides further support for the IOP-lowering proof of concept.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityQuestioned
No rodent carcinogenicity bioassays; applicant cited the ICH S1A ocular-route provision
Why: ICH S1A: ocular-route products may not need carcinogenicity studies; reviewer found 26-week rat and monkey ocular results concerning · Within the guideline
“As justification for not conducting carcinogenicity studies, the Applicant: o Cited ICH S1A42, “Pharmaceuticals administered by the ocular route may not need carcinogenicity studies unless there is cause for concern or unless there is significant systemic exposure.””
“The results of the 26-week rat subcutaneous toxicity study, and the monkey topical ocular studies, are concerning.”
GenotoxicityAccepted with a conditionBeyond the letter
In vivo rat micronucleus test with inadequate dose selection; adequate in vivo genotoxicity test to be required
Why: Adequate in vivo genotoxicity test recommended as a postmarketing requirement under ICH S2(R1)
“The in vivo rat micronucleus test (report # 02-226) dose selection was inadequate.”
“P/T recommends that an adequate in vivo test for genotoxicity be required, consistent with ICH S2(R1).”
Safety marginVerdict not stated
No NOAEL identified in the 39-week monkey topical ocular study
“The GLP monkey 39-week topical ocular toxicity study with omidenepag isopropyl did not identify a NOAEL.”
OtherQuestioned
Rat subcutaneous toxicity studies did not include nasal cavity histopathology
“The rat sc studies did not include histopathology of the nasal turbinates / nasal cavity.”
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